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Originally published online as doi:10.1189/jlb.0209052 on August 17, 2009

Published online before print August 17, 2009
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(Journal of Leukocyte Biology. 2009;86:1319-1329.)
© 2009 Society for Leukocyte Biology

CCR1-mediated activation of nuclear factor-{kappa}B in THP-1 monocytic cells involves pertussis toxin-insensitive G{alpha}14 and G{alpha}16 signaling cascades

Maggie M. K. Lee and Yung H. Wong1

Department of Biochemistry, the Molecular Neuroscience Center, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

1. Correspondence: Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. E-mail: boyung{at}ust.hk

ABSTRACT

Agonists of CC chemokine receptor CCR1 contribute to the pathogenesis of autoimmune and other inflammatory diseases, possibly via the regulation of the transcription factor NF-{kappa}B. CCR1 and CCR2b have been demonstrated to use PTX-insensitive G{alpha}14 and G{alpha}16 to stimulate PLCβ in cotransfected cells, and G{alpha}14 and G{alpha}16 are capable of activating NF-{kappa}B. The coexpression of G{alpha}14, G{alpha}16, and CCR1 in human monocytic THP-1 cells suggests that CCR1 may use G{alpha}14 or G{alpha}16 to induce NF-{kappa}B activation. Here, we demonstrated that a CCR1 agonist, Lkn-1, stimulated NF-{kappa}B phosphorylation via PTX-insensitive G proteins in THP-1 cells. Lkn-1 also mediated IKK/NF-{kappa}B phosphorylations in HEK293 cells overexpressing CCR1 and G{alpha}14/16. Using various kinase inhibitors, Raf-1, MEK1/2, PLCβ, PKC, CaM, CaMKII, and c-Src were found to participate in Lkn-1-stimulated IKK/NF-{kappa}B phosphorylations in THP-1 and transfected HEK293 cells. Although c-Jun N-terminal kinase and p38 MAPK were activated by Lkn-1, they were not required in Lkn-1-induced IKK phosphorylation. The ability of CCR1 to signal through G{alpha}14/16 thus provides a linkage for chemokines to regulate NF-{kappa}B-dependent responses.

Key Words: chemokine • leukotactin-1 • G protein • inhibitor {kappa}B kinase • signal transduction